title: Presence of SPINK-1 variant alters the course of chronic pancreatitis.
abstract: OBJECTIVE
  There is growing evidence that genetic mutations/variants increase susceptibility to the development and progression of chronic pancreatitis (CP). Several mutations have been identified that have a direct and indirect role in events leading to CP. Mutations in the serine protease inhibitor, Kazal type-1 (SPINK-1) gene have been reported to lower the threshold for pancreatitis in the presence of other genetic or environmental factors. The prevalence and impact of SPINK-1 mutations on the clinical course and outcomes of CP remains unclear. This study was conducted to assess the prevalence of the SPINK-1/N34S variant in patients with CP, and to understand the impact of the SPINK-1 mutation on the natural history of CP.
  
  
  METHODS
  A retrospective-prospective analysis of 239 patients with CP was performed. A detailed history, including duration of symptoms, type of pain (intermittent flares or chronic continuous pain), number of flares requiring hospital admission, alcohol and smoking history, and family history was obtained. The baseline morphological stage of CP was categorized by Cambridge classification. Clinical outcome variables included frequency and severity of pain episodes, presence of exocrine failure (defined by presence of steatorrhea and/or fecal elastase < 200 ug/g), and diabetes. The genetic tests included the cationic trypsinogen gene-1 mutation, cystic fibrosis gene mutations (Genzyme assay), and the SPINK-1/N34S mutation.
  
  
  RESULTS
  Of the 239 patients with CP, 13 (5.4%) were positive for the SPINK-1/N34S mutation. There were 35 (14.6%) patients with idiopathic pancreatitis (IP) in this cohort. Most of the patients who were positive for the SPINK-1/N34S mutation had IP and were Caucasian (69.2%). The patients with the SPINK-1/N34S mutation had a younger age of onset (32.9 ± 10.2 vs 40.1 ± 13.6 years; P = 0.108) than those with IP and no mutation. Over a median follow up of 9.6 years, the patients with the SPINK-1/N34S mutation had a significantly greater number of acute flares each year, as compared to those without the mutation (11.8 ± 1.5 vs 4 ± 0.98; P = 0.0001).
  
  
  CONCLUSIONS
  The prevalence of the SPINK-1/N34S mutation in patients with CP is 5.4%, and is approximately 37.1% in patients with IP. These mutations are more prevalent in Caucasian patients with CP. The SPINK-1/N34S mutation predisposes to early onset IP and more frequent acute flares of pancreatitis that might ultimately lead to pancreatic insufficiency. The patients with IP and borderline alcohol history should be considered for testing for genetic analysis, including SPINK-1 mutations, initially restricted to clinical trials.
authors.affiliation: Department of Gastroenterology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23233, USA. bsandhu@vcu.edu
authors.forename: Bimaljit
authors.initials: B
authors.lastname: Sandhu
authors.forename: Patrik
authors.initials: P
authors.lastname: Vitazka
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferreira-Gonzalez
authors.forename: Arti
authors.initials: A
authors.lastname: Pandya
authors.forename: Ravi
authors.initials: R
authors.lastname: Vachhani
authors.forename: Doumit
authors.initials: D
authors.lastname: Bouhaidar
authors.forename: Alvin
authors.initials: A
authors.lastname: Zfass
authors.forename: Arun
authors.initials: A
authors.lastname: Sanyal
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D050500:Pancreatitis, Chronic / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014768:Virginia; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic